The enzyme plasma kallikrein, also known by the classification EC.3.4.21.34, is a member of a family of trypsin-like serine protease that also includes tissue kallikrein, thrombin, trypsin and plasmin. It is found in plasma as an inactive zymogen that is activated by Factor XIIa. The enzyme has a broad spectrum of activity. Plasma kallikrein liberates the vasoactive peptide bradykinin from high molecular weight kininogen by cleavage of Lys-Arg and Arg-Ser bonds. The same peptide can also be liberated from low molecular weight kininogen in the presence of neutrophil elastase. It is also capable of activating prourokinase and plasminogen, and is also thought to participate in the conversion of prorenin to renin. Plasma kallikrein is an essential component of the intrinsic blood coagulation cascade although its role does not involve the release of bradykinin or enzymatic cleavage. High molecular weight kininogen, the preferred substrate for plasma kallikrein, is essential for the activation in this cascade (K. D. Bhoola et al., Pharm. Rev., 1992, 44, 1-80).
The physiological effects of plasma kallikrein are likely to result from the proteolytic cleavage of kininogens to liberate kinins or of other substrates, e.g. precursors of growth factors. Kinins such as bradykinin are potent mediators of inflammation. In addition they influence cellular functions such as blood pressure, local blood flow, glucose transport and cell proliferation. These cellular actions which are modified by release of secondary messengers such as platelet activating factor, leukotrienes, prostaglandins, Substance P, acetylcholine and noradrenaline.
Several groups have disclosed synthetic inhibitors of plasma kallikrein. These include arginine ketomethylene derivatives (WO 92/04371 and D. M. Evans et al., Immunopharmacology, 1996, 32, 115-116), noragmatine and agmatine derivatives (WO 95/07291, WO 94/29335), benzamidine derivatives (J. Stürzbecher et al., Brazilian J. Med. Biol. Res. 1994, 27, 1929-1934), boronic acid derivatives (U.S. Pat. No. 5,187,157) and aminomethylcyclohexanoyl derivatives (N. Teno et al., Chem. Pharm. Bull., 1993, 41, 1079-1090). The aminomethylcyclohexanoyl derivatives have been shown to be active in models of collagen-induced arthritis in mice (Y. Fujimora et al., Agents Actions, 1993, 39, 42-48) and endotoxin-induced disseminated intravascular coagulation (DIC) in rats (S. Okamoto et al., Agents Actions (Supplement), 1992, 38 (Part 1), 198-205). The boronic acid derivatives are active in models of inflammatory bowel disease (A. Stadnicki et al., Digestive Diseases and Sciences, 1996, 41, 912-920 and FASEB, 1998, 12,325-333).
Selectivity with respect to the other members of the trypsin-like serine protease family is an important issue. Inhibitors of tissue kallikrein displaying poor plasma kallikrein activity have previously been reported (M. Szelke et al., Brazilian J. Med. Biol. Res. 1994, 27, 1935 and D. M. Evans et al., Immunopharmacology, 1996, 32, 117), but there remains a need for compounds that selectively inhibit plasma kallikrein and not tissue kallikrein.